9-Deoxy-5,9α-epoxy-5,6-didehydro-PGF1 amides

ABSTRACT

The present invention relates to novel 9-deoxy-5,9αepoxy-5,6-didehydro-PGF 1  amides, which are useful for inducing a variety of prostacyclin-like pharmacological effects. Accordingly, these compounds are useful pharmacological agents for the same purposes for which prostacyclin is employed.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a divisional application of U.S. Pat. No. 932,899, filed Aug. 11, 1978, now pending issuance as a U.S. patent; which is a divisional application of U.S. Ser. No. 819,856, filed July 28, 1977, now U.S. Pat. No. 4,123,441; which is a continuation-in-part application of U.S. Ser. No. 725,546, filed Sept. 22, 1976, now abandoned; which is a continuation-in-part application of U.S. Ser. No. 716,960, filed Aug. 23, 1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel 9-deoxy-5,9α-epoxy-5,6-didehydro-PGF₁ amides, which are useful for inducing a variety of prostacyclin-like pharmacological effects. Accordingly, these compounds are useful pharmacological agents for the same purposes for which prostacyclin is employed.

The essential material constituting a disclosure of the preparation and use of the novel compounds of the present invention is incorporated here by reference from U.S. Pat. No. 4,123,441.

SUMMARY OF THE INVENTION

The present invention particularly provides:

a 4Z compound of the formula ##STR1##

wherein W₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;

wherein L is --(CH₂)_(d) --C(R₂)₂,

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro;

wherein Q is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive;

wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring;

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof; and a 4E compound of the formula ##STR2##

wherein W₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;

wherein L is --(CH₂)_(d) --C(R₂)₂, wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro;

wherein Q is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive;

wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); where Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ - and the phenyl ring;

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

With regard to the divalent substituents described in the claims, e.g., Q and W₁, these divalent radicals are defined as α-R_(i) :β-R_(j), where R_(i) represents a substituent of the divalent moiety of the alpha configuration with respect to the cyclopentane and R_(j) represents a substituent of the divalent moiety of the beta configuration with respect to the cyclopentane ring. Accordingly, when Q is defined as α-OH:β-R₈, the hydroxy of the Q moiety is in the alpha configuration, i.e., as in prostacyclin, and the R₈ substituent is in the beta configuration. Not all carbon atoms to which such divalent moieties are attached represent asymmetric centers. For example, when both valence bonds are to hydrogen (e.g., W₁ or Q is α-H:β-H), then no asymmetric center is present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following chemical compounds:

(4Z)-9-deoxy-5,9α-epoxy-Δ4-11-deoxy-16-phenoxy-17,18,19,20-tetranor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-17-phenyl-18,19,20-trinor-13,14-didehydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-phenoxy-17,18,19,20-trinor-13,14-didehydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-17-phenyl-18,19,20-trinor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-17-phenyl-18,19,20-trinor-cis-13-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-phenoxy-17,18,19,20-tetranor-cis-13-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-(p-fluorophenoxy)-17,18,19,20-tetranor-13,14-dihydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-(m-chlorophenoxy)-17,18,19,20-tetranor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-(p-fluorophenoxy)-17,18,19,20-tetranor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor-cis-13-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16,16-dimethyl-17-phenyl-18,19,20-trinor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16-methyl-16-phenoxy-18,19,20-trinor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-16,16-difluoro-17-phenyl-18,19,20-trinor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-2,2-difluoro-17-phenyl-18,19,20-trinor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-PGF₁, amide;

(4Z)-9-deoxy-5,9α-epoxy-Δ4-2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-PGF₁, amide; and

(4Z)-9-deoxy-5,9α-epoxy-Δ4-2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-PGF₁, amide. 

I claim:
 1. A compound of the formula ##STR3## wherein W₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;wherein L is --(CH₂)_(d) --C(R₂)₂, wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro; wherein Q is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive; wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; andwherein X is (1) trans--CH═CH--, (2) cis--CH═CH--,(3) --C.tbd.C--, or (4) --CH₂ CH₂ --; including the lower alkanoates thereof.
 2. A compound according to claim 1, wherein W₁ is α-H:β-OH.
 3. A compound according to claim 1, wherein W₁ is oxo.
 4. A compound according to claim 1, wherein W₁ is methylene.
 5. A compound according to claim 1, wherein W₁ is α-H:β-H.
 6. A compound according to claim 5, wherein L is --(CH₂)_(n) --, n being 2, 3, or 4, and wherein Q is oxo or α-OH:β-R₈, wherein R₈ is limited to hydrogen, methyl, or ethyl.
 7. A compound according to claim 1, wherein W₁ is α-CH₂ OH:β-H.
 8. A compound according to claim 1, wherein W₁ is α--OH:β--H.
 9. A compound according to claim 8, wherein L is --(CH₂)_(n) --, n being 2, 3, or 4, and wherein Q is oxo or α-OH:β-R₈, wherein R₈ is hydrogen, methyl, or ethyl.
 10. A compound according to claim 9, wherein L is --CH₂ CH₂ --.
 11. A compound according to claim 10, wherein R₅ and R₆ are hydrogen.
 12. A compound according to claim 11, wherein s is zero.
 13. A compound according to claim 8, wherein X is --C.tbd.C--.
 14. A compound according to claim 8, wherein X is --CH₂ CH₂ --.
 15. A compound according to claim 9, wherein X is trans--CH═CH--.
 16. A compound according to claim 8, wherein X is cis--CH═CH--.
 17. A compound according to claim 11, wherein s is one.
 18. A compound according to claim 17, wherein X is --CH₂ CH₂ --.
 19. A compound according to claim 17, wherein X is trans--CH═CH--.
 20. A compound according to claim 17, wherein X is cis--CH═CH--.
 21. A compound according to claim 10, wherein R₅ and R₆ are methyl.
 22. A compound according to claim 21, wherein s is zero.
 23. A compound according to claim 22, wherein X is --CH₂ CH₂ --.
 24. A compound according to claim 22, wherein X is trans--CH═CH--.
 25. A compound according to claim 22, wherein X is cis--CH═CH--.
 26. A compound according to claim 10, wherein R₅ and R₆ are fluoro.
 27. A compound according to claim 26, wherein s is zero.
 28. A compound according to claim 27, wherein X is --CH₂ CH₂ --.
 29. A compound according to claim 27, wherein X is trans--CH═CH--.
 30. A compound according to claim 8, wherein L is --CH₂ CF₂, and wherein Q is oxo or αOH:β-R₈, wherein R₈ is hydrogen, methyl, or ethyl.
 31. A compound according to claim 30, wherein R₅ and R₆ are hydrogen.
 32. A compound according to claim 31, wherein s is zero.
 33. A compound according to claim 32, wherein X is --CH₂ CH₂ --.
 34. A compound according to claim 32, wherein X is trans--CH═CH--.
 35. A compound according to claim 32, wherein X is cis--CH═CH--.
 36. A compound according to claim 30, wherein R₅ and R₆ are methyl.
 37. A compound according to claim 36, wherein s is zero.
 38. A compound according to claim 37, wherein X is --CH₂ CH₂ --.
 39. A compound according to claim 37, wherein X is trans--CH═CH--.
 40. A compound according to claim 37, wherein X is cis--CH═CH--.
 41. A 4E compound of the formula ##STR4## wherein W₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H, α-CH₂ OH:β-H;wherein L is --(CH₂)_(d) --C(R₂)₂, wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro; wherein Q is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; and wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms, inclusive; wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--), a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; andwherein X is (1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --; including the lower alkanoates thereof. 